ABAD enhances Aβ‐induced cell stress via mitochondrial dysfunction

Abstract

Amyloid-beta peptide (Abeta) binding alcohol dehydrogenase (ABAD), an enzyme present in neuronal mitochondria, is a cofactor facilitating Abeta-induced cell stress. We hypothesized that ABAD provides a direct link between Abeta and cytotoxicity via mitochondrial oxidant stress. Neurons cultured from transgenic (Tg) mice with targeted overexpression of a mutant form of amyloid precursor protein and ABAD (Tg mAPP/ABAD) displayed spontaneous generation of hydrogen peroxide and superoxide anion, and decreased ATP, as well as subsequent release of cytochrome c from mitochondria and induction of caspase-3-like activity followed by DNA fragmentation and loss of cell viability. Generation of reactive oxygen species (ROS) was associated with dysfunction at the level of mitochondrial complex IV (cytochrome c oxidase, or COX). In neurons cultured from Tg mAPP/ABAD mice, COX activity was selectively decreased, and cyanide, an inhibitor of complex IV, exacerbated leakage of ROS, induction of caspase-3-like activity, and DNA fragmentation. In vivo, Tg mAPP/ABAD mice displayed reduced levels of brain ATP and COX activity, diminished glucose utilization, as well as electrophysiological abnormalities in hippocampal slices compared with Tg mAPP mice. In contrast, neither Tg ABAD mice nor nontransgenic (non-TG) littermates showed similar changes in ATP, COX activity, glucose utilization or electrophysiological properties. Each of the genotypes (Tg ABAD, Tg mAPP and Tg mAPP/ABAD mice, and non-TG littermates) displayed normal reproductive fitness, development and lifespan (1) These findings link ABAD-induced oxidant stress to critical aspects of Alzheimer's disease (AD)-associated cellular dysfunction, suggesting a pivotal role for this enzyme in the pathogenesis of AD.

Ovariectomy increases neuronal amyloid-β binding alcohol dehydrogenase level in the mouse hippocampus

“…In addition, we recently elucidated that the interaction of ABAD and Aβ caused mitochondrial dysfunction leading to neuronal apoptosis (Lustbader et al, 2004;Takuma et al, 2005). Interestingly, the present study demonstrated that OVX for 5 weeks increased neuronal ABAD level in the mouse hippocampus.…”

The mitochondrial impairment, oxidative stress and neurodegeneration connection: reality or just an attractive hypothesis?

“…Unlike other respiratory complexes, complex IV has the capacity to retain partially reduced, unstable intermediates during electron transport, and therefore it is not considered a site of ROS production [47]. However, COX inhibition could lead to a backup of reduced complexes upstream in the respiratory chain, which has been proposed to increase ROS production [48][49][50].…”

“…The proposed mechanisms of complex IV inhibition by Aβ include (i) blockage of mitochondrial import channels by APP to prevent the import of nuclear-encoded complex IV subunits [66], (ii) sequestration of heme by Aβ [67,68] and (iii) interaction between Aβ and Aβ-binding alcohol dehydrogenase (ABAD) [50,69]. The latter two mechanisms have been suggested to promote ROS production.…”

Mitochondria impairment correlates with increased sensitivity of aging RPE cells to oxidative stress

“…There is compelling evidence that mitochondrial dysfunction is an early event in Alzheimer's and Parkinson's disease supporting claims that age-related mitochondrial dysfunction is an upstream event in many neurodegenerative disorders [18][19][20][21]. This is underscored in studies showing that amyloid precursor protein transgenic mice have decreased mitochondrial membrane potential, lowered ATP-levels and higher ROS levels, altered Bcl-xL/Bax ratio, reduced COX IV activity, and an overall decrease in mitochondrial respiratory function at a stage when there is no detectable level of amyloid-beta deposits in the brain [22].…”